Endurance exercise is cardioprotective against ischemia-reperfusion (I-R) injury. Previously identified mediators of cardioprotection include antioxidants, antioxidant enzymes, heat shock proteins, and iNOS suggesting that exercise-induced cardioprotection is a polygenic phenomenon. Recent data demonstrate that the inducible form of cyclooxygenase (COX-2), and subsequent prostanoid production (PGE2 and PGI2), is cardioprotective. Data from our laboratory indicate that COX-2 activity is dramatically increased in exercise trained rats. The cardioprotective impact of an exercise-induced increase in COX-2 activity, however, is unknown. The objective of this proposal is to elucidate the effects of endurance exercise on COX-2-mediated cardioprotection. The applicant will test the hypothesis that exercise-mediated cardioprotection against I-R myocardial stunning and infarction is dependent upon increased myocardial COX-2 activity and its prostanoid metabolites. Exercise mediated cardioprotection in rats will be evaluated in response to stunning and infarction insults. An I-R stunning challenge will be performed using the isolated working heart model while I-R infarction will be performed in vivo. In both models, COX-2 activity will be blocked by selective pharmacological inhibitors. Measures of myocardial performance will be used as correlates to markers of COX-2 activity and myocardial damage. This project should produce important new insights into mechanisms exercise-induced cardioprotection in addition to the role of COX-2 in general cardiac pathophysiology. [unreadable] [unreadable]